The long term goal of this project is to gain an understanding of the molecular basis of cardiac excitability, concentrating on molecular structure-function relationships of cardiac K+ channels. The hypotheses to be tested are that specific regions and even specific amino acid residues are implicated in activation and deactivation gating and rectification of cardiac K channels. The specific aims to be investigated include: (1) test of whether or not an extracellular ring of positive charges in hKv1.5 is a molecular determinant of outward rectification, (2) test whether or not the sixth transmembrane domain (S6) comprises part of the activation gate, This information should advance our understanding of the molecular physiology and pharmacology of cardiac K channels and further help in correlating cloned subunits with membrane currents in native cardiac cells. Finally, the information gained will expand our knowledge of the function of this important class of K channels, which may ultimately result in improved understanding of the genesis of cardiac arrhythmias and the development of better antiarrhythmic agents.